RYZ101 (225Ac-DOTATATE) in patients with estrogen receptor-positive, human epidermal growth factor receptor 2–negative, locally advanced and unresectable, or metastatic breast cancer progressing after prior therapy: The phase 1b/2 TRACY-1 study.
Background: RYZ101 (actinium-225 [225Ac]-DOTATATE) is a radiolabeled somatostatin analog (SSA) for the treatment of patients with solid tumors expressing somatostatin receptor-type 2 (SSTR2). RYZ101 is composed of the alpha-emitting radioisotope 225Ac, the chemical chelator DOTA (tetraxetan), and SSA octreotate (TATE). RYZ101 binds with high affinity to SSTR2 on the cell surface and is internalized, whereupon the alpha-particle emission of 225Ac results in lethal double-strand DNA breaks. Although SSTR-directed therapy is widely used in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs), its relevance in non-GEP-NET SSTR-expressing neoplasms is still emerging. Clinical positron emission tomography (PET) imaging studies have reported SSTR expression in estrogen receptor (ER)-positive breast cancer. Available data support investigating the efficacy of RYZ101 in patients with ER-positive, HER2-negative, locally advanced and unresectable or metastatic breast cancer. Methods: TRACY-1 (NCT06590857) is a global, multicenter, open-label, two-part (dose escalation and expansion) phase 1b/2 study. Key inclusion criteria are: age ≥18 years; histologically confirmed, ER-positive, HER2-negative locally advanced and unresectable or metastatic breast cancer not amenable to curative-intent treatment; endocrine-refractory disease; documented progression (per RECIST v1.1) after ≥2 and ≤4 prior lines of chemotherapy and/or ADC (≥1 must be ADC if the patient is a candidate for ADCs and treatment is available); ≥1 RECIST-measurable SSTR−PET-positive lesion and ≥80% of RECIST-measurable lesions being SSTR−PET-positive on screening scan. Key exclusion criteria are: prior radiopharmaceutical therapy; prior anticancer therapy or external beam radiotherapy in past 4 weeks; anticancer hormonal treatments in past 2 weeks. Primary objectives are to determine the recommended phase 2 dose (R2PD) of RYZ101 (dose escalation; anticipated 6−24 patients), and the efficacy of RYZ101 at the RP2D defined as ORR as determined by BICR (dose expansion; approximately 100 patients). During dose escalation, patients will receive RYZ101 by IV infusion every 6 weeks for up to 6 cycles at a starting dose of 6.5 MBq (dose level [DL] 1), with escalation to DL 2 (8.3 MBq) and DL 3 (10.2 MBq), or dose de-escalation to 4.6 MBq if DL 1 is not tolerated, based on dose-limiting toxicity rates. In the expansion phase, patients will receive RYZ101 at the RP2D. Concomitant amino acid IV infusions (containing L-arginine and L-lysine) will be co-infused with RYZ101 for renal protection. The study is ongoing and enrolling patients in the USA.
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Author Details
Erica Mayer
Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Abstract Details
Meeting
2025 ASCO Annual Meeting
Session Type
Poster Session
Session Title
Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
Track
Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
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